---
kind: "section"
citation: "21 U.S.C. § 356a"
title: "21"
title_heading: "Food and Drugs"
number: "356a"
heading: "Manufacturing changes"
release: "119-102"
date: "2026-07-12"
url: "https://uscodex.org/usc/21/356a"
units:
  - "Chapter 9 — Federal Food, Drug, and Cosmetic Act"
  - "Subchapter V — Drugs and Devices"
  - "Part A — Drugs and Devices"
---

# §356a. Manufacturing changes

- (a) **In general—** With respect to a [drug](/usc/21/321.md?p=g-1) for which there is in effect an approved application under section [355](/usc/21/355.md) or [360b](/usc/21/360b.md) of this title or a license under [section 262 of title 42](/usc/42/262.md), a change from the manufacturing process approved pursuant to such application or license may be made, and the [drug](/usc/21/321.md?p=g-1) as made with the change may be distributed, if—
  - (1) the holder of the approved application or license (referred to in this section as a “holder”) has validated the effects of the change in accordance with [subsection (b)](#b); and
  - (2)
    - (A) in the case of a major manufacturing change, the holder has complied with the requirements of [subsection (c)](#c); or
    - (B) in the case of a change that is not a major manufacturing change, the holder complies with the applicable requirements of [subsection (d)](#d).
- (b) **Validation of effects of changes—** For purposes of [subsection (a)(1)](#a-1), a [drug](/usc/21/321.md?p=g-1) made with a manufacturing change (whether a major manufacturing change or otherwise) may be distributed only if, before [distribution](/usc/21/360eee.md?p=5) of the [drug](/usc/21/321.md?p=g-1) as so made, the holder involved validates the effects of the change on the identity, strength, quality, purity, and potency of the [drug](/usc/21/321.md?p=g-1) as the identity, strength, quality, purity, and potency may relate to the safety or effectiveness of the [drug](/usc/21/321.md?p=g-1).
- (c) **Major manufacturing changes—**
  - (1) **Requirement of supplemental application—** For purposes of [subsection (a)(2)(A)](#a-2-A), a [drug](/usc/21/321.md?p=g-1) made with a major manufacturing change may be distributed only if, before the [distribution](/usc/21/360eee.md?p=5) of the [drug](/usc/21/321.md?p=g-1) as so made, the holder involved submits to the [Secretary](/usc/21/321.md?p=d) a supplemental application for such change and the [Secretary](/usc/21/321.md?p=d) approves the application. The application shall contain such information as the [Secretary](/usc/21/321.md?p=d) determines to be appropriate, and shall include the information developed under [subsection (b)](#b) by the holder in validating the effects of the change.
  - (2) **Changes qualifying as major changes—** For purposes of [subsection (a)(2)(A)](#a-2-A), a major manufacturing change is a manufacturing change that is determined by the [Secretary](/usc/21/321.md?p=d) to have substantial potential to adversely affect the identity, strength, quality, purity, or potency of the [drug](/usc/21/321.md?p=g-1) as they may relate to the safety or effectiveness of a [drug](/usc/21/321.md?p=g-1). Such a change includes a change that—
    - (A) is made in the qualitative or quantitative formulation of the [drug](/usc/21/321.md?p=g-1) involved or in the specifications in the approved application or license referred to in [subsection (a)](#a) for the [drug](/usc/21/321.md?p=g-1) (unless exempted by the [Secretary](/usc/21/321.md?p=d) by regulation or guidance from the requirements of this subsection);
    - (B) is determined by the [Secretary](/usc/21/321.md?p=d) by regulation or guidance to require completion of an appropriate clinical study demonstrating equivalence of the [drug](/usc/21/321.md?p=g-1) to the [drug](/usc/21/321.md?p=g-1) as manufactured without the change; or
    - (C) is another type of change determined by the [Secretary](/usc/21/321.md?p=d) by regulation or guidance to have a substantial potential to adversely affect the safety or effectiveness of the [drug](/usc/21/321.md?p=g-1).
- (d) **Other manufacturing changes—**
  - (1) **In general—** For purposes of [subsection (a)(2)(B)](#a-2-B), the [Secretary](/usc/21/321.md?p=d) may regulate [drugs](/usc/21/321.md?p=g-1) made with manufacturing changes that are not major manufacturing changes as follows:
    - (A) The [Secretary](/usc/21/321.md?p=d) may in accordance with [paragraph (2)](#d-2) authorize holders to [distribute](/usc/21/360eee.md?p=5) such [drugs](/usc/21/321.md?p=g-1) without submitting a supplemental application for such changes.
    - (B) The [Secretary](/usc/21/321.md?p=d) may in accordance with [paragraph (3)](#d-3) require that, prior to the [distribution](/usc/21/360eee.md?p=5) of such [drugs](/usc/21/321.md?p=g-1), holders submit to the [Secretary](/usc/21/321.md?p=d) supplemental applications for such changes.
    - (C) The [Secretary](/usc/21/321.md?p=d) may establish categories of such changes and designate categories to which [subparagraph (A)](#d-1-A) applies and categories to which [subparagraph (B)](#d-1-B) applies.
  - (2) **Changes not requiring supplemental application—**
    - (A) **Submission of report—** A holder making a manufacturing change to which [paragraph (1)(A)](#d-1-A) applies shall submit to the [Secretary](/usc/21/321.md?p=d) a report on the change, which shall contain such information as the [Secretary](/usc/21/321.md?p=d) determines to be appropriate, and which shall include the information developed under [subsection (b)](#b) by the holder in validating the effects of the change. The report shall be submitted by such date as the [Secretary](/usc/21/321.md?p=d) may specify.
    - (B) **Authority regarding annual reports—** In the case of a holder that during a single year makes more than one manufacturing change to which [paragraph (1)(A)](#d-1-A) applies, the [Secretary](/usc/21/321.md?p=d) may in carrying out [subparagraph (A)](#d-2-A) authorize the holder to comply with such subparagraph by submitting a single report for the year that provides the information required in such subparagraph for all the changes made by the holder during the year.
  - (3) **Changes requiring supplemental application—**
    - (A) **Submission of supplemental application—** The supplemental application required under [paragraph (1)(B)](#d-1-B) for a manufacturing change shall contain such information as the [Secretary](/usc/21/321.md?p=d) determines to be appropriate, which shall include the information developed under [subsection (b)](#b) by the holder in validating the effects of the change.
    - (B) **Authority for distribution—** In the case of a manufacturing change to which [paragraph (1)(B)](#d-1-B) applies:
      - (i) The holder involved may commence [distribution](/usc/21/360eee.md?p=5) of the [drug](/usc/21/321.md?p=g-1) involved 30 days after the [Secretary](/usc/21/321.md?p=d) receives the supplemental application under such paragraph, unless the [Secretary](/usc/21/321.md?p=d) notifies the holder within such 30-day period that prior approval of the application is required before [distribution](/usc/21/360eee.md?p=5) may be commenced.
      - (ii) The [Secretary](/usc/21/321.md?p=d) may designate a category of such changes for the purpose of providing that, in the case of a change that is in such category, the holder involved may commence [distribution](/usc/21/360eee.md?p=5) of the [drug](/usc/21/321.md?p=g-1) involved upon the receipt by the [Secretary](/usc/21/321.md?p=d) of a supplemental application for the change.
      - (iii) If the [Secretary](/usc/21/321.md?p=d) disapproves the supplemental application, the [Secretary](/usc/21/321.md?p=d) may order the [manufacturer](/usc/21/360hh.md?p=3) to cease the [distribution](/usc/21/360eee.md?p=5) of the [drugs](/usc/21/321.md?p=g-1) that have been made with the manufacturing change.

## Source credit

(June 25, 1938, ch. 675, § 506A, as added Pub. L. 105–115, title I, § 116(a), Nov. 21, 1997, 111 Stat. 2313.)

## Notes

### Statutory Notes and Related Subsidiaries

### Effective Date

Pub. L. 105–115, title I, § 116(b), Nov. 21, 1997, 111 Stat. 2315, provided that: “The amendment made by subsection (a) [enacting this section] takes effect upon the effective date of regulations promulgated by the Secretary of Health and Human Services to implement such amendment, or upon the expiration of the 24-month period beginning on the date of the enactment of this Act [Nov. 21, 1997], whichever occurs first.”